Poly(2-oxazolines) in biological and biomedical application contexts

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N. Adams, U.S. Schubert / Advanced Drug Delivery Reviews 59 (2007) 1504–1520 1515 polymers, the organic solvent used in the dialysis experiment and the weight ratio of drug to polymer. In experiments, the toxicity of the polymer was found to be insignificant when compared to other matrices such as Tween 80 and comparable to Cremophore EL (polyoxyethylated castor oil, CreEL). Paclitaxel containing micelles were shown to inhibit the growth of KB cells (cell line derived from a human carcinoma of the nasopharynx) to the same extent as comparable CreEL formulations (but with reduced toxicity of the carrier). Hsiue et al. reported the synthesis of a series of hydrogels based on poly(2-ethyl-2-oxazoline) and three-armed poly(D,L-lactide) [132]. The polymers were prepared via photochemical crosslinking of three-arm poly(D,L-lactide-trimethacrylate) (3PLA– TMA) and poly(2-ethyl-2-oxazoline) dimethacrylate (PEOXA– DMA) (Fig. 12). All of the resulting hydrogels were sensitive to both pH as well as temperature stimuli and showed a high degree of water retention. Consistent with the corresponding linear systems (see above), gels derived from the cross-linked polymer show thermonegative swelling behavior and low swelling at low pH. Scanning electron micrographs showed, that the degree of crosslinking has a significant effect on the particle and pore size. Polymers consisting only of cross-linked polyoxazoline give rise to uniformly spherical particles and porous structures. Introduction of the poly(caprolactone) units lead to smaller particles in the case of low PCL content and to uniform surfaces without discernible pores at higher concentrations. The photochemical cross-linking of telechelic PEOXA bearing acrylate groups on both chain ends leads to networks, which have a highly soluble component [133]. The observed cloud point for the cross-linked species is, as expected, somewhat lower than that for a completely linear PEOXA of similar molecular weight. When attempting to reduce the amount of soluble fraction via the addition of an equimolar amount of ethyleneglycol dimethacrylate with respect to the macromonomer, a hydrogel with a significantly decreased cloud point (when compared to the pure PEOXA gels) was obtained. Furthermore, different swelling behaviors were observed. In an attempt to control the LCST behavior, the researchers prepared segmented networks by free-radical copolymerisation of PEOXA macromonomer with hydroxyethyl methacrylate (HEMA), 2-hydroxypropyl acrylate (HPA) or methyl methacrylate (MMA). As a general rule, the LCST behavior of the resulting networks depends on the hydrophilicity/hydrophobicity of the comonomer and the fraction of PEOXA present in the networks. Like the cross-linked systems described above, linear poly(Llactide)-block-poly(2-ethyl-2-oxazoline)-block-poly(L-lactide) polymers show thermonegative behavior in aqueous solution and even precipitate from solution in the temperature range between 33 and 38 °C [134]. The latter is explained by a combination of dehydration of the PEOXA segments and the aggregation of the hydrophobic PLLA segments. Furthermore, acid-base titrations indicated, that the triblocks show considerable buffering capacity over the whole pH range. At room temperature, they are protonated and exist as polycations, which could make them potentially suitable candidates for gene delivery applications. PLLA-block-PEOXA-block-PLLA has also been shown to be a promising candidate for the delivery of the anti-cancer drug doxorubicin (DOX) [135]. In aqueous solution the polymer forms flower-like micelles, which can be loaded with the DOX active ingredient. At physiological pH (7.4) and in vitro, the Fig. 12. Synthesis of (A) 3-arm poly(D,L-lactide) trimethacrylate and (B) poly(2-ethyl-2-oxazoline) dimethacrylate [132].
1516 N. Adams, U.S. Schubert / Advanced Drug Delivery Reviews 59 (2007) 1504–1520 release of doxorubicin is essentially suppressed, while at pH 5 the drug is released from the micelles, due to micellar deformation: micelles are taken up by cells via endocytosis with the endocytosed particles usually being transported to the lysosome. V-ATPases subsequently pump protons into the particle, which lowers the pH to 5 [136]. As PLLA-block- PEOXA-block-PLLA is pH sensitive, this leads to a deformation of the micellar structure and the release of DOX inside the cell, which causes apoptosis. PLLA-block-PEOXA-block- PLLA is biocompatible and shows virtually no cytotoxicity even at high concentration, thus allowing for high doses of the polymer to be administered. The somewhat easier-to-prepare PLLA-block-PEOXA diblock copolymer showed very similar behavior, although it was found to be more cytotoxic than the corresponding triblock as well as showing a higher release of doxorubicin at physiological pH [137]. PLLA-block-PEOXAblock-PLLA has recently been shown to be degradable by proteinase K [138]. Poly(2-isopropyl-2-oxazoline) (PIOXA), whose repeat unit is isomeric to that of poly(N-isopropyl acrylamide), has also attracted attention as a smart material. Like the other polyoxazolines it shows a thermonegative behavior in aqueous solution and undergoes reversible phase separation in the temperature range from 45 to 63 °C, depending on the molecular weight of the polymer. Differential scanning calorimetry showed that the phase transition is endothermic, with the enthalpy of transition ranging from 1.51 kJ/mol to 5.64 kJ/mol depending on molecular weight [139]. Consistent with previous observations, the presence of sodium chloride ions lowers the phase transition temperature and increases the transition enthalpy. Pressure perturbation calorimetry demonstrates the extreme sensitivity of the solvation volume w.r.t. the polymer chain length, nearly doubling in value for a polymer with a DP of 50 compared with a poly(2-isopropyl-2-oxazoline) oligomer with a DP of 17. This, in turn, indicates that the number of hydrogen-bonding positions along the chain increases with increasing molecular weight. Further studies using telechelic and heterotelechelic poly(2-isopropyl-2-oxazolines) end-functionalized by hydroxy, amine or acetal groups furthermore show that the cloud points of these polymers are highly concentration dependent [140]. However, when comparing the cloud point temperatures for 1.0 M solutions of acetal-PIOXA-OH (M n =9600, M n /M w =1.15) with that of Me- PIOXA-OH (M n =9700, M n /M w =1.02), nearly identical values are found, indicating that under these circumstances, the molecular weight is the determining factor for the thermal response of these polymer. Further work by Kataoka et al. showed, that the LCST of amphiphilic poly(2-isopropyl-2-oxazoline) can be accurately tuned by copolymerisation with a hydrophilic 2-ethyl-2-oxazoline comonomer [141]. The researchers prepared simple gradient copolymers of the two components in such a way as to gradually decrease the ethyl oxazoline content along the chain, while increasing the isopropyl oxazoline content from the α-terminal to the ω-terminal chain end. Experiments investigating the thermosensitive behavior of the resulting gradient copolymers showed, that the LCST increases linearly with the mole percentage of ethyl oxazoline over a broad temperature range from 38.7 to 67.3 °C. Consistent with previous observations, the presence of sodium chloride lowers the LCST temperature. The tuning of LCST behavior via compositional variation has also been demonstrated for poly(chloromethylstyrene-co-N-isopropylacrylamide-graft-2- alkyl-2-oxazoline) polymers [142]. The materials were synthesized by cationic ring-opening polymerisation of 2-methyl or 2-ethyl-2- oxazoline initiated by random copolymers of chloromethylstyrene and N-isopropyl acrylamide, acting as macroinitiators. The polymers showed transition temperatures in the range of 28 to 40 °C, with the increase in the observed transition temperature being proportional to the amount of alkyl oxazoline units in the side chain, relative to the amount of NIPAAm units in the main chain, provided that the same macroinitiator is used. The observed transition can be explained in terms of the initial intramolecular collapse of the polymer backbone, followed by an intermolecular aggregation of the polymer as the solution approaches the transition temperature, ultimately leading to precipitation of the polymer. If the content of long polyoxazoline grafts is sufficiently high, stabilized aggregates with thermoresponsive cores are formed at the transition temperature and no precipitation is observed. Recently, Schlaad and Meyer reported the synthesis of poly (2-isopropyl-2-oxazoline)-block-poly(L-glutamate) in an effort to combine the temperature-sensitive properties of the poly(2- isopropyl-2-oxazoline) with the pH sensitivity of the poly(Lglutamate) [143]. Unfortunately, no data on the stimulussensitive behavior of these polymers is currently available. In a similar fashion, Winnik and colleagues report the synthesis of poly(2-ethyl-2-oxazoline)-block-hyaluronan copolymers and speculate that these should have temperature-sensitive properties. However, no actual data has been provided [144]. 2.5. Antimicrobial polymers Antimicrobial polymers are becoming increasingly important materials in the face of spreading microbial infections and increasing microbial resistance to antibiotics [145]. Research in this area has been conducted since the late 1970s. Most systems tend to be based on quarternary ammonium salts [146] which are covalently attached to a polymer, although biguanide [147], phosphonium [148] and sulphonium [149] salts have also been used. The proposed mode of action of all of these cationic species is a disruption of the cytoplasmic membrane, which leads to a release of potassium ions as well as constituents of the membrane and subsequent cell death. Waschinski et al. recently reported the synthesis of a series of PMOXA and PEOXA polymers, terminated with quarternary ammonium groups [150]. The polymers were prepared via standard cationic ring-opening polymerisation and terminated using a series of N-alkyl-N,N-dimethyl amines as well as pyridine. The materials were subsequently evaluated w.r.t. their antimicrobial properties by determining the minimal inhibitory concentration against Staphylococcus aureus. The screening showed, that only poly(2-methyl-2-oxazoline)-based polymers containing alkyl ammonium functions with alkyl chains of twelve carbon atoms or longer have any antimicrobial activity
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